Signaling through the insulin-like growth factor 1 receptor (IGF-1R) is increasingly recognized as a precursor to and a potentiator of the malignant phenotype in preclincal models. The axis of proteins involved is complex, including two ligands, six binding proteins, IGF-1R, and IGF-2R, a non-signaling receptor, and two adaptor proteins. Circulating levels or tumor expression of IGF axis proteins has been correlated with risk of malignancy or poor prognosis of established cancer. IGF-1R interacts with other cellular receptors including epidermal growth factor receptor (EGFR), a validated drug target in HNSCC. We have observed that activation of IGF-1R signaling in cell lines promotes proliferation, survival, angiogenesis and invasion. Further, our data indicate that activation of IGF-1R can mediate resistance to EGF-R-targeted therapy and vice versa, suggesting an advantage to co-targeting EGFR and IGF-1 R. Thus, we hypothesize that cotargeting IGF-1 R and EGFR will be more successful than inhibition of either pathway alone in therapy of HNSCC. In this project, we will assess IGF axis protein expression and downstream proteins in tumor microarrays from patients resected for SCC of the oral tongue (Aim 1). Correlation of biomarkers with disease-specific survival will be explored, especially as regards the negative impact of nodal spread and extracapsular invasion, an invasive phenotype. We will study cooperation of IGF-1 R and EGFR in mediating proliferative, angiogenic, and invasive activities of HNSCC lines in vitro (Aim 2). Antitumor effects of the anti- IGF-1R humanized monoclonal antibody (IMC-A12) will be studied alone or with anti-EGFR antibody cetuximab, using multiple complementary models, including a highly metastatic cell line, in orthotopic tongue xenograft models (Aim 3). The activity of IMC-A12 as monotherapy or combined with cetuximab will be defined in a randomized trial for patients with recurrent HNSCC (Aim 4), targeting a 50% improvement in progression-free survival compared to cetuximab alone. Tissue and blood-based biomarkers will be assessed and correlations with clinical outcomes explored. This proposal builds on our results implicating IGF axis signaling in potentiating the malignant phenotype of HNSCC and promising data co-targeting EGFR and IGF-1 R in therapy of HNSCC. Insights to be gained from this work, both preclincal and clinical aims, have the potential to facilitate targeting therapy to those patients most likely to benefit.